SCOR Project 4 uses basic biophysical techniques to elucidate the normal interfacial properties and activity of pulmonary surfactant and its phospholipid and apoprotein components, and how they can be compromised by endogenous inactivators such as plasma proteins during lung disease or injury. In addition to obtaining a better understanding of surfactant activity and dysfunction, a major focus of this project is also to define effective synthetic exogenous surfactant substitutes that can be used in replacement therapy for the neonatal Respiratory Distress Syndrome (RDS) and for acute lung injury syndromes (ARDS). The research proceeds through a series of inter-related specific aims involving: 1) characterizations of the interfacial properties, interactions, and phase and bi-layer behavior of mixtures containing phospholipids combined with purified surfactant apoproteins SP-A,B and C or with synthetic hydrophobic peptides having varying degrees of structural homology to SP-A,B and -C; 2) similar biophysical studies with a series of novel phospholipid analog compounds, synthesized with defined structural differences to allow the definition of molecular structure-surface activity correlates for phospholipid-like molecules; 3) interfacial studies, including mechanistic assessments, of the biophysical inactivation of natural and synthetic lung surfactants by endogenous inhibitors including plasma proteins, membrane lipids, meconium and others relevant for clinical lung injuries; and 4) mechanical (pressure-volume) studies of surfactant activity in excised lungs, in the presence and absence of specific inactivators, to define the physiological activity of exogenous surfactants, and to generate biophysical- physiological correlates of surfactant activity and dysfunction. The studies stressed in this research are largely fundamental in nature, and utilize a spectrum of biophysical techniques including interfacial activity studies of dynamic surface tension lowering, respreading and hysteresis using Wilhelmy balance and oscillating bubble methodology, plus adsorption measurements. Additional molecular-level biophysical information is gained by X-ray diffraction, differential scanning calorimetry (DSC), MASS proton and 13C NMR, and ultra-high resolution field emission scanning electron microscopy (FSEM). Basic biophysical and physiological information gained on SCOR Project 4 is utilized to help guide and interpret the pathophysiological and biochemical studies of lung injury in animal models in SCOR Project 9, and the clinical studies of Project 10.